Suppression of IFN-β production by Epstein-Barr virus lytic transactivator Zta

Abstract

Interferon β (IFN-β) production is an innate antiviral immune response against virus infection and lytic virus production. Several molecular mechanisms, including the sensing of cytosolic double-stranded DNA (dsDNA) by cyclic GMP-AMP synthase (cGAS), have been described to induce IFN-β production. Epstein-Barr virus (EBV) is a γ-herpesvirus that infects most of the population in the world and is associated with the development of various lymphoid and epithelial malignancies in a subset of people. In this study, we identified and characterized EBV lytic transactivator Zta as a potent suppressor of IFN-β production. EBV lytic infection was shown to suppress IFN-β production. To identify the viral proteins that mediate this suppression, a functional screen was performed using a dual-luciferase reporter system and an expression library of all EBV proteins. In this screen EBV lytic transactivator Zta was found to be capable of potently suppressing IFN-β production induced by different stimuli of interferon regulatory factor 3 (IRF3) activation. Zta is previously known to directly interact with and suppress IRF7, but its impact on IRF3 and the mode of action have not been demonstrated. We showed that Zta prevented the activation of IRF3 and IFN-β promoter by cGAS and STING (stimulator of interferon genes). Mechanistically, Zta suppressed the phosphorylation of IRF3 and its upstream interacting partner TANK-binding kinase 1 (TBK1), leading to the inhibition of IRF3 activity and nuclear translocation. Therefore, Zta may help EBV to evade host immunity during lytic infection by circumventing IRF3 activation and thus IFN-β production. Our findings revealed a new mechanism for EBV evasion of innate immunity.